Chronic obstructive pulmonary disease (COPD) is prevalent, costly and associated with high morbidity and mortality. It is also a remarkably heterogeneous condition with regards to both its pulmonary and systemic manifestations. The mechanistic underpinnings of this heterogeneity remain poorly understood and treatment approaches for patients with COPD are still mostly the same. Metabolomics is the large-scale study of low molecular weight compounds, commonly known as metabolites, within cells, tissues or biological fluids. Preliminary data suggest that specific metabolomics profiles are associated with poor clinical outcomes in COPD and may reveal unique insights into disease heterogeneity. Such investigations could ultimately lead to the development of new therapeutic approaches which are sorely needed. However, the potential of metabolomics remains largely untapped in COPD. This K23 mentored career development application proposes a coordinated 5-year training and research plan to allow Wassim Labaki, MD, MS to achieve his long-term goal of becoming an independent physician-scientist. His scientific focus will be on patient-oriented clinical and translational COPD research, specifically in the field of metabolomics. Dr. Labaki will be mentored and advised by experts not only in metabolomics, but also bioinformatics and clinical research to help him hone such skills during the award period. His training plan will include advanced coursework at the University of Michigan School of Public Health and Department of Computational Medicine and Bioinformatics, further supplemented by hands-on practical experience in the metabolomics laboratories at the University of Michigan and regular participation in various national and institutional workshops and conferences. This application will take advantage of the clinically well-characterized NIH-funded SPIROMICS COPD cohort to identify mechanistic metabolic pathways involved in COPD pathogenesis and progression that could be intervened upon early in the disease course. The specific Aims of this project are to: 1) define the serum metabolomics profiles associated with COPD phenotypes, especially the frequent exacerbator phenotype; 2) determine the relationship between longitudinal changes in the serum metabolome and progression of COPD over 5 years of follow-up; and 3) investigate the impact of reduction in hyperinflation via lung volume reduction surgery on the serum metabolome. The work planned in this proposal leverages the unique infrastructure and expertise of the Michigan Regional Comprehensive Metabolomics Resource Core at the University of Michigan. The preliminary data and rigorous training acquired through the successful completion of this proposal will position Dr. Labaki to lead targeted metabolomics validation studies and clinical trials in future R01 applications.